What is the appropriate diagnostic workup for type 1 diabetes mellitus?

Diagnosis of Type 1 Diabetes Mellitus

Type 1 diabetes is diagnosed by demonstrating hyperglycemia using standard glucose or HbA1c criteria, then confirming autoimmune β-cell destruction through islet autoantibody testing. 1

Step 1: Establish Hyperglycemia

Any one of the following criteria confirms hyperglycemia:

• Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) after at least 8 hours without caloric intake 2, 1
• 2-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during a 75-gram oral glucose tolerance test 2, 1
• HbA1c ≥6.5% (48 mmol/mol) measured in an NGSP-certified laboratory 2, 1
• Random plasma glucose ≥200 mg/dL (11.1 mmol/L) in a patient with classic symptoms of hyperglycemia 2, 1

Classic symptoms include: polyuria, polydipsia, unexplained weight loss, polyphagia, fatigue, and blurred vision. 1

Confirmation Requirements

• If classic symptoms or hyperglycemic crisis are present: A single abnormal test is sufficient for immediate diagnosis 1, 3
• If hyperglycemia is not unequivocal: Two abnormal test results are required—either repeat the same test on different days or use two different tests, each exceeding its threshold 2, 1, 3

Critical Limitations of HbA1c

Do not use HbA1c for diagnosis in these conditions—use plasma glucose criteria only: 2, 3

• Sickle cell disease or other hemoglobinopathies
• Pregnancy (second and third trimesters)
• G6PD deficiency
• Hemodialysis
• Recent blood loss or transfusion
• Erythropoietin therapy

Point-of-care HbA1c devices must not be used for diagnosis. 2, 3

Step 2: Confirm Type 1 Diabetes with Autoantibody Testing

Once hyperglycemia is established, measure islet autoantibodies to distinguish type 1 from other forms of diabetes. 1

Autoantibody Testing Algorithm

1. Start with glutamic acid decarboxylase (GAD) antibodies—positive in approximately 80% of type 1 diabetes cases 1
2. If GAD is negative, test for:
   • Islet antigen-2 (IA-2) antibodies 1
   • Zinc transporter-8 (ZnT8) antibodies 1
   • Insulin autoantibodies (IAA)—useful only before insulin therapy is started 1

The presence of two or more positive islet autoantibodies confirms type 1 diabetes. 1

Important caveats:

• 5–10% of adult-onset type 1 diabetes cases are autoantibody-negative 1
• Autoantibodies must be measured in an accredited laboratory with established quality control 1
• Multiple positive autoantibodies indicate higher risk of progression to insulin dependence 1

Step 3: Assess β-Cell Function with C-Peptide (When Needed)

C-peptide testing helps differentiate type 1 from type 2 diabetes in ambiguous cases, particularly in adults. 1

C-Peptide Interpretation

• Fasting C-peptide <0.3 ng/mL (<200 pmol/L): Suggests severe insulin deficiency consistent with type 1 diabetes 1
• Random C-peptide >600 pmol/L (>1.8 ng/mL): Strongly argues against type 1 diabetes, indicating preserved β-cell function 1
• Values between 200–600 pmol/L: Indeterminate; may be seen in type 1, MODY, or insulin-treated type 2 diabetes 1

Critical timing: Do not measure C-peptide within 2 weeks of a hyperglycemic emergency (DKA or HHS), as results will be falsely low. 1

Three-Stage Classification System

Type 1 diabetes develops through three distinct stages: 1

Stage	Autoantibodies	Glycemic Status	Clinical Features
Stage 1	≥2 positive	Normoglycemia	Presymptomatic
Stage 2	≥2 positive	Dysglycemia (FPG 100–125 mg/dL, 2-h OGTT 140–199 mg/dL, or HbA1c 5.7–6.4%)	Presymptomatic
Stage 3	≥2 positive	Overt hyperglycemia meeting diagnostic criteria	Symptomatic disease requiring insulin

1

Special Considerations for Children

In children with classic symptoms (polyuria, polydipsia, weight loss) and random glucose ≥200 mg/dL, diagnosis is confirmed immediately without repeat testing. 1

For oral glucose tolerance testing in children: Use 1.75 g/kg body weight (maximum 75 g) of glucose. 2, 1

Critical pitfall: Incidental hyperglycemia in acutely ill children often reflects stress hyperglycemia, not new-onset diabetes. 1 However, the metabolic state of untreated children with true type 1 diabetes can deteriorate rapidly—do not delay diagnosis or insulin initiation when type 1 diabetes is suspected. 1

Screening for Presymptomatic Type 1 Diabetes

Autoantibody screening in asymptomatic individuals is recommended only for: 1

• First-degree relatives of people with type 1 diabetes
• Participants in research studies

Detection of multiple confirmed islet autoantibodies predicts progression to clinical diabetes and warrants referral to a specialized center for evaluation and possible enrollment in clinical trials or approved therapies (e.g., teplizumab) to delay disease onset. 1

Common Diagnostic Pitfalls

• Do not assume obesity excludes type 1 diabetes—obesity can coexist with autoimmune β-cell destruction 1
• Do not rely solely on age—nearly half of type 1 diabetes cases are diagnosed in adulthood 1, 4
• Do not assume negative autoantibodies rule out type 1 diabetes—5–10% of cases are autoantibody-negative 1
• Plasma glucose samples must be centrifuged and separated immediately after collection to prevent glycolysis-induced falsely low results 3
• In rapidly evolving type 1 diabetes in children, HbA1c may not be significantly elevated despite frank diabetes 2